The traditional approach to drug development involves the identification of a target and the empirical testing of a group of compounds for their activity relative to that target. The group of compounds selected for empirical testing often is very large. For example, the group may include tens of thousands of individual compounds. In some cases the group is limited to modifications of an existing drug or is otherwise narrowed based on what is known about the chemical structure of the target. Eventually, most of the compounds are eliminated and a small group of compounds passes to later stages of the development process, such as to clinical trials.
The cost of empirically testing thousands of compounds can be very high. Furthermore, there is a growing body of information about the chemical mechanisms behind drug activity. Thus, there is a trend toward rational drug design, which involves using known information to narrow the group of candidate compounds and thereby lower the cost of empirical screening. In rare cases, enough information is known to design specific chemical structures with the desired biological activity.
Greater knowledge about what chemical properties cause compounds to interact in various ways with biological structures will facilitate rational drug design. Redox potential is an example of a chemical property that may be of interest for its effect on biological activity. For example, Marinov, B. S., et al., “Redox Properties of Local Anesthetics: A Structural Determination of Closed Channel Blockers in BTX-Modified Na+ Channels,” MEMBER CELL BIOL. 14(4):553-63 (2001) (Marinov) provides evidence that the “redox properties of tetracaine, benzocaine, and their homologs correlate with their ability to enhance Na+ channel inactivation in BTX-modified Na+ channels.”
Knowledge about how certain chemical properties affect biological activity only is useful if compounds having such properties can be readily identified. Existing techniques for measuring redox activity are limited. For example, cyclic voltammetry (an electrochemical method) has been used to evaluate the redox properties of compounds by monitoring the exchange of electrons between the compounds and electrodes in solution. This method usually requires relatively large concentrations of the subject compound, which may be difficult to obtain. Moreover, many weak redox-active compounds do not directly exchange electrons with an electrode. Weak redox-active compounds also cannot be detected with certain conventional chemical probes, such as cytochrome C and dithionitrobenzoate.
Marinov describes testing the redox properties of local anesthetics by their “ability to donate electrons to radical intermediates of eosin dye excited by visible light.” This method is limited, however, at least in part because it involves testing under anaerobic conditions. Alternative methods for evaluating the redox properties of compounds are needed.